Ionic mechanisms underlying cardiac toxicity of the organochloride solvent trichloromethane

Trichloromethane (chloroform) is widely used for industrial chemical synthesis and also as an organic solvent in laboratories or ingredient of pesticides. Sudden death resulted from cardiac arrhythmias has been reported in clinic with acute trichloromethane intoxication. The present study was designed to investigate ionic mechanisms underlying arrhythmogenic effect (cardiac toxicity) of trichloromethane in isolated rat hearts and ventricular myocytes and HEK 293 cells stably expressing human Nav1.5, HCN2, or hERG channel using conventional electrophysiological approaches. It was found that trichloromethane (5 mM) induced bradycardia and atrial-ventricular conduction blockade or ventricular fibrillation, and inhibited cardiac contractile function in isolated rat hearts. It shortened action potential duration (APD) in isolated rat ventricular myocytes, and increased the threshold current for triggering action potential, but had no effect on the inward rectifier K+ current IK1. However, trichloromethane significantly inhibited the L-type calcium current ICa.L and the transient outward potassium current Ito in a concentration-dependent manner (IC50s: 1.01 and 2.4 mM, respectively). In HEK 293 cells stably expressing cardiac ion channel genes, trichloromethane reduced hNav1.5, HCN2, and hERG currents with IC50s of 8.2, 3.3, and 4.0 mM, respectively. These results demonstrate for the first time that trichloromethane can induce bradycardia or ventricular fibrillation, and the arrhythmogenic effect of trichloromethane is related to the inhibition of multiple ionic currents including ICa.L, Ito, INa, HCN2, and hERG channels.

► Chloroform is widely used for industrial chemical synthesis and organic solvent.
► Sudden death is related to lethal arrhythmias in clinic with chloroform intoxication.
► Bradycardia and ventricular fibrillation are observed in isolated rat hearts.
► The arrhythmogenic effect of chloroform is resulted from multiple ion channel blockade.